The immune system can normally distinguish “self” from “non-self”. Some immune system cells (lymphocytes) become sensitized against “self” tissue cells, but are normally controlled by other lymphocytes. When the normal control process is disrupted, allowing lymphocytes to avoid suppression, or when there is an alteration in some body tissue so that it is no longer recognized by the immune system as “self”, autoimmune disorders develop. The mechanisms that cause disrupted control or tissue alterations are not well known. One theory holds that various microorganisms and drugs may trigger some of these changes, particularly in people with genetic predisposition to autoimmune disorders. There are a number of autoimmune diseases including, for example, multiple sclerosis (MS), rheumatoid arthritis (RA), and Type I diabetes.
Type I diabetes is a progressive autoimmune disease, in which the beta cells that produce insulin are slowly destroyed by the body's own immune system. White blood cells called T lymphocytes produce immune factors called cytokines that attack and gradually destroy the beta cells of the pancreas. Important cytokines are interleukin-1-beta, tumor necrosis factor-alpha, and interferon-gamma. Specific proteins are also critical in the process. They include glutamic acid decarboxylase (GAD), insulin, and islet cell antigens. These proteins serve as autoantigens. That is, they trigger the self attack of the immune system on its body's own beta cells. It is unknown what first starts this cascade of immune events, but evidence suggests that both a genetic predisposition and environmental factors, such as a viral infection, are involved.
As a result of autoimmune diabetes, the pancreas produces little or no insulin, and insulin must be injected daily for the survival of the diabetic. Insulin, a hormone produced by the pancreas, is needed to convert sugar, starches and other food into glucose and to make it available to the body's cells for energy. In muscle, adipose (fat) and connective tissues, insulin facilitates the entry of glucose into the cells by an action on the cell membranes. The ingested glucose is normally converted in the liver to CO2 and H2O (50%); to glycogen (5%); and to fat (30-40%), the latter being stored in fat depots. Fatty acids from the adipose tissues are circulated, returned to the liver for re-synthesis of triacylglycerol and metabolized to ketone bodies for utilization by the tissues. The fatty acids are also metabolized by other organs. Fat formation is a major pathway for carbohydrate utilization. The net effect of insulin is to promote the storage and use of carbohydrates, protein and fat.
Some complications arising from long-standing diabetes are vascular disease, microvascular disease, eye complications, diabetic nephropathy, diabetic neuropathy, diabetic foot problems, and skin and mucous membrane problems. The action of Type 1 diabetes is to cause hyperglycemia (elevated blood glucose concentration) and a tendency towards diabetic ketoacidosis (DKA). Currently treatment requires chronic administration of insulin. Sporadic or persistent incidence of hyperglycemia can be controlled by administering insulin. Uncontrolled hyperglycemia can further damage the cells of the pancreas which produce insulin (the β-islet cells) and in the long term create greater insulin deficiencies.
Type 1 diabetes (Insulin dependent diabetes mellitus, IDDM) represents 20% of all human diabetes, and is the most serious form of the disease, with highest morbidity an mortality. Up to 800,000 people in the US are estimated to have type 1 diabetes, with about 30,000 new cases diagnosed each year. In addition., the incidence of IDDM has been rising over the past few decades in certain regions of the US and some European countries, particularly in Finland and England.
Currently, oral sulfonylureas and insulin injections are the only two therapeutic agents available in the United States for treatment of Diabetes mellitus. Both agents have the potential for producing hypoglycemia as a side effect, reducing the blood glucose concentration to dangerous levels. There is no generally applicable and consistently effective means of maintaining an essentially normal fluctuation in glucose levels in DM. The resultant treatment attempts to minimize the risks of hypoglycemia while keeping the glucose levels below a target value. The drug regimen is combined with control of dietary intake of carbohydrates to keep glucose levels in control. However, to date, there has been no cure for many autoimmune disorders, including type 1 diabetes. Clearly, a strong need exists for new, more effective treatments for these diseases.